PROJECT SUMMARY In the US, major birth defects affect a delivery every 4 minutes and the morbidity and mortality of tens of thousands of children annually. An environmental (i.e. non-inherited) exposure or causal gene variant is estimated to explain about one-third of all defects that occur. Since 1996, the Iowa Center for Birth Defects Research and Prevention (CBDRP) has played a leadership role in surveillance and research of major birth defects. Our partnerships with the Iowa Department of Public Health and Iowa Registry for Congenital and Inherited Disorders provide comprehensive and timely surveillance of deliveries to Iowa residents. With these partnerships, we successfully enrolled mothers in the National Birth Defects Prevention Study (NBDPS) and Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) I. Using exposure data and biologic specimens collected, we made substantial contributions to birth defects epidemiology, ranging from methods development to identifying gene-environment interaction effects. Our work has provided critical insights into birth defect etiology and been disseminated in high-impact journals. We propose to expand the work of the Iowa CBDRP through successful participation in the BD-STEPS II. Our overall goal is to identify modifiable maternal exposures in early pregnancy, which may increase the risk for having a pregnancy affected with a major birth defect. We will expertly conduct comprehensive and timely data collection and reporting for the BD- STEPS II using our highly experienced surveillance and research infrastructures. Our proposed research approach is not only consistent with the BD-STEPS II required activities, but expands and innovates the conceived study design (RFA-DD-18-001). We propose to address critical barriers identified in a recent review of the NBDPS to investigate modifiable risk factors for major birth defects. To accomplish this, we will expand the traditional epidemiology approach (used in the NBDPS and BD-STEPS) by integrating a multiomics systems epidemiology approach. Our systems approach is novel in its application to NBDPS and BD-STEPS data. It will use state of the art genomic analysis to lead to improved characterization of the case phenome and improved delineation of pathways that influence birth defect development via the exposome. The expertise of our key personnel and collaborating investigators, along with access to rich exposure and biologic data from independent populations, provides us with unique resources among all CBDRPs, allowing us to successfully implement our systems approach. Additionally, we will continue our leadership role and expand our training of a future generation of birth defect researchers. Along with continuing to train pre-doctoral and postdoctoral scholars, we will now include bachelor?s scholars. Our key personnel, investigators, and scholars will continue our high productivity in disseminating findings from NBDPS and BD-STEPS through peer-reviewed publications. Research findings generated will provide critical insights into modifiable risk factors for major birth defects and be used for family education, treatment improvements, and application of prevention strategies.